Diamino pyridine derivatives

ABSTRACT

The present invention describes novel diamino pyridine derivatives exhibiting JAK modulating properties. The present invention also relates to pharmaceutical compositions comprising these novel compounds, methods of using said compounds in the treatment of various diseases and disorders being susceptible to JAK modulation, and processes for preparing the compounds described hereinafter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 U.S. National Phase Application ofInternational Application Number PCT/IB2016/057105 filed 24 Nov. 2016,which application claims the benefit of priority under 35 U.S.C. §119(a) to European Application No. 15196542.3, filed 26 Nov. 2015. Thedisclosures of which are incorporated herein by reference in theirentirety and for all purposes.

The present invention describes novel diamino pyridine derivativesexhibiting JAK modulating properties. The present invention also relatesto pharmaceutical compositions comprising these novel compounds, methodsof using said compounds in the treatment of various diseases anddisorders being susceptible to JAK modulation, and processes forpreparing the compounds described hereinafter.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I) orpharmaceutically acceptable salts thereof, and to their use inmodulating JAK. Hence the compounds of the invention may be useful inthe treatment of diseases and/or disorders susceptible to JAKmodulation. Such diseases and/or disorders typically include inter aliaatopic dermatitis, psoriasis and other diseases and/or disorders e.g. asdescribed hereinafter. The present invention further relates topharmaceutical compositions comprising e.g. novel diamino pyridinederivatives of formula (I), methods of using said compounds in thetreatment of various diseases and disorders, and processes for preparingthe said novel compounds.

BACKGROUND OF THE INVENTION

Signal transduction initiated by multiple cytokines and growth factorreceptors is mediated by dedicated non-receptor tyrosine kinases of theJanus kinase (JAK) family. The four members of this family (JAK 1-3 andTyk2) are multi-domain proteins of about 130 kDa and are highlyhomologous with respect to their domain structure. The catalytic kinasedomain located at the C-terminus is preceded by a pseudokinase domain, aSrc homology 2 (SH2) domain and the N-terminal FERM (four-point-one,ezrin, radixin and moesin homology) domain. The latter serves tofacilitate the interaction between the JAK protein and the cytokinereceptor. According to the canonical signaling pathway ligand binding totheir cognate receptor triggers engagement of JAK kinases which, in aseries of phosphorylation events targeting the receptor, the JAK'sthemselves and one or several of the 6 representatives of the STAT(signal transducer and activator of transcription) family members relaythe signal into the cells. Phosphorylated STATs dimerize and migrate tothe nucleus where they become part of transcriptional regulatorycomplexes which lead to transcription of responsive genes. The canonicalJAK-STAT signaling pathway is evolutionary conserved and is active inmultiple cell types where it is utilized by a variety of hormones,growth factors and cytokines and their receptors. This key signalingpathway has been elucidated over the last 25 years and has been thesubject of multiple excellent reviews. See Cytokine receptors and theinvolvement of JAK kinases (from Cox and Cools, Chemistry & Biology 18,Mar. 25, 2011).

Due to their key roles in multiple cytokine pathways, JAK inhibitors arebelieved to be of therapeutic value for diseases in which JAK-dependentsignaling is pathologically augmented. Inhibition of the four JAKkinases may represent an attractive therapeutic strategy for treatingdiseases and/or disorders associated with dysregulation of the immunesystem. Systemic as well as organ-restricted inhibition of JAK signalingis considered to be of high therapeutic value.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of formula (I) and/orpharmaceutically acceptable salts thereof, and to their use ofmodulating JAK, and may further include inter alia the treatment ofdiseases and/or disorders such as allergic diseases, airway diseases,such as asthma and chronic obstructive pulmonary disease (COPD),rheumatoid arthritis, systemic onset juvenile idiopathic arthritis(SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura,systemic lupus erythematosus, multiple sclerosis, myasthenia gravis,Sjögren's syndrome, thrombotic thrombocytopenic purpura, chronicautoimmune urticaria, allergy (atopic dermatitis, contact dermatitis,allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes,inflammatory bowel disease, ulcerative colitis, morbus Crohn,pancreatitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto'sthyroiditis, Grave's disease, antibody-mediated transplant rejection(AMR), graft versus host disease, B cell-mediated hyperacute, or acuteand chronic transplant rejection.

More particularly, in embodiment 1 the present invention relates to acompound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein,R₁ is H or C₁-C₆ alkyl; andHal is halogen.

DETAILED DESCRIPTION OF THE INVENTION

In its broadest embodiment (embodiment 1) the present invention relatesto a compound of formula (I) and/or a pharmaceutically acceptable saltthereof as described above in the section Summary of the Invention.

Embodiment 2 of the present invention relates to a compound ofembodiment 1 or a pharmaceutically acceptable salt thereof, wherein Halis chloro or fluoro.

Embodiment 3 of the present invention relates to a compound ofembodiment 1, or a pharmaceutically acceptable salt thereof, wherein Halis chloro.

Embodiment 4 of the present invention relates to a compound ofembodiment 1, 2, or 3, or a pharmaceutically acceptable salt thereof,wherein R₁ is methyl.

Embodiment 5 of the present invention relates to a compound ofembodiment 1, 2, or 3, or a pharmaceutically acceptable salt thereof,wherein R₁ is hydrogen.

Embodiment 6 of the present invention relates to a compound ofembodiment 1, 2, 3, or 4 or a pharmaceutically acceptable salt thereof,wherein R₁ is methyl in position 6 of the associated pyridine ring.

Embodiment 7 of the present invention relates to a compound ofembodiment 1 or 4 or a pharmaceutically acceptable salt thereof, whichis selected from4-((2-chlorophenyl)amino)-6-(pyridin-2-ylamino)nicotinamide; and4-((2-chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinamide.

Embodiment 8 relates to a pharmaceutical composition comprising atherapeutically effective amount of a compound according to any one ofembodiments 1 to 7 and one or more pharmaceutically acceptable carriers.

Embodiment 9 relates to a combination comprising a therapeuticallyeffective amount of a compound according to any one of embodiments 1 to7 or a pharmaceutically acceptable salt thereof and one or moretherapeutically active co-agents.

Embodiment 10 relates to a method of modulating JAK activity in asubject, wherein the method comprises administering to the subject atherapeutically effective amount of the compound according to any one ofembodiments 1 to 7 or a pharmaceutically acceptable salt thereof.

Embodiment 11 relates to a compound according to any one of embodiments1 to 7 or a pharmaceutically acceptable salt thereof, for use as amedicament.

Definitions

As used herein, the term “C₁-C₆ alkyl” refers to a fully saturatedbranched or unbranched hydrocarbon moiety having up to 6 carbon atoms.Unless otherwise provided, it refers to hydrocarbon moieties having 1 to6 carbon atoms, 1 to 4 carbon atoms or 1 to 2 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo; and it may in particular refer to chloro, fluoro.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate,chloride/hydrochloride, citrate, fumarate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,sulfosalicylic acid, and the like. The pharmaceutically acceptable saltsof the present invention may be synthesized from a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate or the like), or by reacting free baseforms of these compounds with a stoichiometric amount of the appropriateacid. Such reactions are typically carried out in water or in an organicsolvent, or in a mixture of the two. Generally, use of non-aqueous medialike ether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H and ¹⁴C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labeledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically-labeled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by JAK, or (ii) associated with JAK activity, or(iii) characterized by activity (normal or abnormal) of JAK; or (2)reducing or inhibiting the activity of JAK; or (3) reducing orinhibiting the expression of JAK. In another non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofthe compound of the present invention that, when administered to a cell,or a tissue, or a non-cellular biological material, or a medium, iseffective to at least partially reducing or inhibiting the activity ofJAK; or reducing or inhibiting the expression of JAK partially orcompletely.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturateddouble bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention may bein the form of one of the possible rotamers, atropisomers, tautomers,geometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiralstationary phase.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form (including without limitationcapsules, tablets, pills, granules, powders or suppositories), or in aliquid form (including without limitation solutions, suspensions oremulsions). The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e. g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

EXPERIMENTAL PART Abbreviations

BINAP: (2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl)

Cs₂CO₃: Cesium carbonate

DMSO: Dimethyl sulfoxide

g: gram

h: hour

NaHMDS: Sodium bis(trimethylsilyl)amide

min: minutes

MS: Mass spectrometry

mL or ml: milliliter

Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium(0)

THF: Tetrahydrofuran

UPLC: Ultra-performance liquid chromatography

Analytical Methods

Liquid Chromatography:

UPLC/MS: Waters Acquity UPLC+Waters ZQ2000 MS

UV-PDA: 210-450 nM

MS range: 100-1200 Da

Column: Acquity HSS T3 2.1×50 mm 1.8p at 60° C.

Mobile phase: A: water+0.05% formic acid

-   -   B: acetonitrile+0.04% formic acid

Time [min] Flow [ml/min] A [%] B [%] 0.00 1.000 95 5 1.40 1.000 2 981.80 1.000 2 98 1.90 1.000 95 5 2.00 1.000 95 5

Synthesis of Intermediate 36-chloro-4-((2-chlorophenyl)amino)nicotinamide

At 0° C. a 1 M solution of sodium bis(trimethylsilyl)amide (NaHMDS) inTHF (340.8 mL) was added dropwise to a solution of 1 (9.3 g, 48.7 mmol)and 2 (7.68 mL, 73 mmol) in THF (100 mL) and the mixture stirred for 3 hat 25° C. under an atmosphere of nitrogen. The mixture was quenched withwater, extracted with ethyl acetate, dried with sodium sulfate andconcentrated under reduced pressure. The crude product was stirred withdiethyl ether (200 mL) for 0.5 h and filtered to give 3 (12.8 g, 95%purity) as a pale yellow solid. MS: 282.0 (M+1)+, ¹H NMR (DMSO-d6)δ=10.84 (1H, s), 8.60 (1H, s), 8.35 (1H, m), 7.80 (1H, m), 7.59 (2H, m),7.41 (1H, m), 7.25 (1H, m), 6.73 (1H, s).

Synthesis of Example 14-((2-chlorophenyl)amino)-6-(pyridin-2-ylamino)nicotinamide

To a stirred solution of 3 (5.9 g, 20.9 mmol) in dioxane (150 mL) wasadded at 25° C. 4 (2.95 g, 31.4 mmol), Cs₂CO₃ (17 g, 52.3 mmol),Pd₂(dba)₃ (1.92 g, 2.09 mmol), BINAP (1.95 g, 3.14 mmol) andtriethylamine (4.4 mL, 31.4 mmol). The resulting solution was degassedand heated at 100° C. for 16 h. The mixture was diluted with water,extracted with ethyl acetate, washed with brine, dried with sodiumsulfate and concentrated under vacuum. Purification by combi flash usinga 40 g Silicycle column (4% methanol in dichloromethane) affordedExample 1 (1.6 g, 98% purity) as an off white solid. Retention time:0.67 min; MS: 340.1 (M+1)⁺; ¹H NMR (DMSO-d6/D20) δ=8.52 (1H, s), 8.11(1H, m), 7.72-7.62 (3H, m), 7.56 (1H, m), 7.41 (2H, m), 7.18 (1H, m),6.90 (1H, m).

Synthesis of Example 24-((2-chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinamide

To a stirred solution of 3 (5.9 g, 20.9 mmol) in dioxane (150 mL) wasadded at 25° C. 5 (3.39 g, 31.4 mmol), Cs₂CO₃ (17 g, 52.3 mmol),Pd₂(dba)₃ (1.92 g, 2.09 mmol), BINAP (1.95 g, 3.14 mmol) andtriethylamine (4.4 mL, 31.4 mmol). The resulting solution was degassedand heated at 100° C. for 16 h. The mixture was diluted with water,extracted with ethyl acetate, washed with brine, dried with sodiumsulfate and concentrated under vacuum. Purification by combi flash usinga 40 g Silicycle column (4% methanol in dichloromethane) affordedExample 2 (2.9 g, 99.5% purity) as an off white solid. Retention time:0.74 min; MS: 354.2 (M+1)⁺; ¹H NMR (DMSO-d6) δ=11.00 (1H, s), 9.74 (1H,m), 8.59 (1H, s), 8.09 (2H, m), 7.70 (1H, d), 7.59 (1H, d), 7.52 (1H,t), 7.43 (1H, t), 7.40 (1H, m), 7.17 (2H, m), 6.72 (1H, d), 2.26 (3H,s).

Biological Part

Enzymatic JAK assays. For enzyme assays affinity-purified GST-fusions ofthe active kinase domains (GST-JAK1 (866-1154), GST-JAK2 (808-1132),GST-JAK3 (811-1124), and GST-TYK2(888-1187) were expressed in insectcells or purchased from Invitrogen (Carlsbad, USA). All assays wereperformed in 384-well microtiter plates with 8-point serial dilutions ofcompounds. The kinase reactions were started by stepwise addition of 4.5μl per well of a 2× peptide/ATP-solution and 4.5 μl per well of a 2×enzyme solution. The final ATP concentration used in the assayscorresponds to the individually determined KmATP for the respectiveenzyme. Assay buffer: 50 mM HEPES, pH 7.5, 1 mM DTT, 0.02% Tween20,0.02% BSA, 0.6% DMSO, 10 mM beta-glycerophosphate, and 10 μM sodiumorthovanadate. Other components were adjusted specifically for therespective kinase assays: JAK1: 16 nM enzyme, 70 μM ATP, 2 μM peptidesubstrate, 12 mM MgCl2. JAK2: 1.8 nM enzyme, 20 μM ATP, 2 μM peptidesubstrate, 9 mM MgCl2. JAK3: 13 nM enzyme, 18 μM ATP, 2 μM peptidesubstrate, 1.5 mM MgCl2. Tyk2: 3.5 nM enzyme, 35 μM ATP, 2 μM peptidesubstrate, 9 mM MgCl2. The stop solution was 100 mM HEPES pH 7.5, 5%DMSO, 0.1% Caliper coating reagent, 10 mM EDTA, and 0.015% Brij35. Thepeptide substrate used in the JAK2 and Tyk2 assays wasFITC-Ahx-KKSRGDYMTMQIG-NH2 and Carboxyfluorescein-Ahx-GGEEEEYFELVKKKKfor the JAK2 and JAK3 assays. Kinase reactions were incubated at 30° C.for 60 minutes and terminated by addition of 16 μl per well of stopsolution. Phosphorylated and unphosphorylated peptides were separatedusing the Caliper microfluidic mobility shift technology on a CaliperLC3000 workstation and kinase activities were calculated from theamounts of formed phospho-peptide.

IC₅₀ Data Determined Via the JAK-Enzyme Assays:

JAK1 JAK2 JAK3 Tyk2 Example 1 18 nM 14 nM  9 nM 14 nM Example 2 12 nM 25nM 15 nM 24 nMUtility Section

The compounds of the present invention are typically useful in theprevention or treatment of disorders or diseases where JAK play a role,for example in diseases or disorders selected from allergic diseases,airway diseases, such as asthma and chronic obstructive pulmonarydisease (COPD), rheumatoid arthritis, systemic onset juvenile idiopathicarthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenicpurpura, systemic lupus erythematosus, multiple sclerosis, myastheniagravis, Sjögren's syndrome, thrombotic thrombocytopenic purpura, chronicautoimmune urticaria, allergy (atopic dermatitis, contact dermatitis,allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes,inflammatory bowel disease, ulcerative colitis, morbus Crohn,pancreatitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto'sthyroiditis, Grave's disease, antibody-mediated transplant rejection(AMR), graft versus host disease, B cell-mediated hyperacute, and acuteor chronic transplant rejection.

Preferably the compounds of the present invention are in particularuseful in the prevention and/or treatment of a disease or a disorderaffecting or mediated by the immune system.

Dosage

For the above uses the required dosage will of course vary depending onthe mode of administration, the particular condition to be treated andthe effect desired. In general, satisfactory results are indicated to beobtained systemically at daily dosages of from about 0.02 to 25 mg/kgper body weight. An indicated daily dosage in the larger mammal, e.g.humans, may be typically in the range from about 0.2 mg to about 2 g,conveniently administered, for example, in divided doses up to fourtimes a day or in retard form. Suitable unit dosage forms for oraladministration may typically comprise from ca.0.1 to 500 mg activeingredient.

Route of Administration

The compounds of the invention may be administered by any conventionalroute, in particular parenterally, for example in the form of injectablesolutions or suspensions, enterally, e.g. orally, for example in theform of tablets or capsules, topically, e.g. in the form of lotions,gels, ointments or creams, or in a nasal or a suppository form. Topicaladministration may for example be to the skin. A further form of topicaladministration may be to the eye. Pharmaceutical compositions comprisinga compound of the invention in association with at least onepharmaceutical acceptable carrier or diluent may be manufactured inconventional manner by mixing with a pharmaceutically acceptable carrieror diluent.

The compounds of the invention may be administered in free form or inpharmaceutically acceptable salt form. Such salts or hydrates may beprepared in conventional manner and may typically exhibit the same orderof activity as the free compounds.

In accordance with the foregoing, the present invention also provides:

(1) A compound of the invention or a pharmaceutically acceptable saltthereof, for use as a pharmaceutical, or for use as a medicament;

(2) A compound of the invention or a pharmaceutically acceptable saltthereof, for use as a JAK modulator, for example for use in any of theparticular indications hereinbefore set forth;

(3) A pharmaceutical composition, e.g. for use in any of the indicationsherein before set forth, comprising a compound of the invention or apharmaceutically acceptable salt thereof, together with one or morepharmaceutically acceptable diluents or carriers therefor;(4) A method for the treatment or prevention of a disease or conditionin which JAK modulation plays a role or is implicated, e.g. for thetreatment of any of particular indication hereinbefore set forth in asubject in need thereof which comprises administering to the subject aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof;(5) The use of a compound of the invention or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment or prevention of a disease or condition in which JAKmodulation plays a role or is implicated; e.g. as indicated above;6) The use of a compound of the invention or a pharmaceuticallyacceptable salt thereof for the treatment or prevention of a disease orcondition in which JAK modulation plays a role or is implicated; e.g. asindicated above.Combinations

The compounds of formula (I) may be administered as the sole activeingredient or in conjunction with, e.g. as an adjuvant to, other drugse.g. immunosuppressive or immunomodulating agents or otheranti-inflammatory agents, e.g. for the treatment or prevention of allo-or xenograft acute or chronic rejection or inflammatory or autoimmunedisorders, or a chemotherapeutic agent, e.g a malignant cellanti-proliferative agent. For example, the compounds of formula (I) maybe used in combination with a calcineurin inhibitor, e.g. cyclosporin Aor FK 506; or a mTOR inhibitor, e.g. rapamycin.

In accordance with the foregoing the present invention further provides:

(7) A method as defined above comprising co-administration, e.g.concomitantly or in sequence, of a therapeutically effective amount ofa) a compound of formula I or a pharmaceutically acceptable saltthereof, and b) a second drug substance, said second drug substancebeing for example for use in any of the particular indicationshereinbefore set forth;(8) A combination, e.g. a kit, comprising a therapeutically effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof, and a second drug substance, said second drug substance beingfor example as disclosed above.

Where a compound of the invention is administered in conjunction withother immunosuppressive/immunomodulatory, anti-inflammatory orantineoplastic agent, e.g. as disclosed above, dosages of theco-administered drug or agent will of course vary depending on the typeof co-drug or -agent employed, or the specific drug or agent used, orthe condition being treated and so forth.

The invention claimed is:
 1. A compound of formula (I) or apharmaceutically acceptable salt thereof;

wherein, R₁ is H or C₁-C₆ alkyl; and Hal is halogen.
 2. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein Hal ischloro or fluoro.
 3. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Hal is chloro.
 4. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R₁ is methyl.5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R₁ is hydrogen.
 6. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R₁ is methyl inposition 6 of the associated pyridine ring.
 7. The compound of claim 1or a pharmaceutically acceptable salt thereof, which is selected from4-((2-chlorophenyl)amino)-6-(pyridin-2-ylamino)nicotinamide; and4-((2-chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinamide.8. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and one or morepharmaceutically acceptable carriers.
 9. A method of inhibiting JAKactivity in a subject, wherein the method comprises administering to thesubject a therapeutically effective amount of the compound according toclaim 1 or a pharmaceutically acceptable salt thereof.
 10. A method forthe treatment of a disease or condition in a subject in need thereof,wherein the disease or condition is selected from asthma, chronicobstructive pulmonary disease (COPD), rheumatoid arthritis, systemiconset juvenile idiopathic arthritis (SOMA), psoriasis, pemphigusvulgaris, atopic dermatitis, contact dermatitis, allergic rhinitis,inflammatory bowel disease, ulcerative colitis, morbus Crohn,antibody-mediated transplant rejection (AMR), graft versus host disease,wherein the method comprises administering to the subject an effectiveamount of a compound according to any one of claim 1 or apharmaceutically acceptable salt thereof.
 11. The method of claim 10,wherein the disease or condition is atopic dermatitis or psoriasis. 12.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R₁ is H or methyl and Hal is chloro or fluoro.
 13. The compoundof claim 1 or a pharmaceutically acceptable salt thereof, wherein R₁ ismethyl and Hal is chloro.
 14. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R₁ is H and Hal ischloro.
 15. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to claim 7 and one or morepharmaceutically acceptable carriers.